The therapy of tumor illnesses with anti-tumor drugs, e.g., among others with cisplatin derivatives, is often accompanied by strong sensations of nausea and the tumors themselves can also cause nausea or emesis. At present, the modern treatment form of strong emesis involves antagonists of serotonin (=5-hydroxytryptamine a=5-HT) receptors of the 5-HT3 type.
Ondansetron hydrochloride can be mentioned as an example of a specific antagonist for both the chemoreceptors as well as the receptors of the gastrointestinal tract. Further 5-HT3 antagonists are granisetron hydrochloride, azasetron hydrochloride, rarnosetron hydrochloride and their bases.
Approximately 1 hour after oral administration and 6 to 20 minutes after an intravenous administration of ondansetron hydrochloride, peak concentrations are present in the plasma. The average elimination half-life for healthy test persons is 3.5 hours and is increased to approximately 7.9 hours in older patients.
Ondansetron is reliable in treating nausea and emesis in patients who have to undergo treatment with anti-tumor drugs such as cisplatin derivatives. As side effects headaches, diarrhea, and temporary abnormalities in liver function tests occur. The dose of ondansetron as a prophylactic measure against vomiting induced by anti-tumor drugs is generally 0.15 mg/kg i.v. three times a day every 4 hours.
From a chemical point of view, ondansetron is the dihydrate of (xc2x1)-1,2,3,9-tetrahydro-9-methy-3-[(2-methyl-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one monohydrochloride.
The molecular formula is C18H19N3O.HCl.2H2O, which corresponds to a molecular weight of 365.9 g.
Ondansetron is metabolized to a large extent in humans but only approximately 5% of a radioactively marked dose can be found in urine. The primary pathway of metabolism is the hydroxylation at the indole ring followed by glucuronization or sulfation.
The pharmacokinetic data summarized in the table were determined with healthy test persons after a single intravenous administration of a dose of 0.15 mg/kg i.v.
The binding of ondansetron to plasma protein is approximately 70% to 76% and this was measured in vitro in the pharmacologically important concentration range of 10 to 500 nglml.
Ondansetron is absorbed wee after oral administration and undergoes a first-pass-metabolism via the liver passage. The relative bioavailability after administration of 8 mg tablets to healthy test persons is approximately 56%.
Since the administration of 5-HT3 antagonists is conducted by parenteral infusion before administration of anti-tumor drugs and since bioavailability is only approximately 50% (e. g., for ondansetron) after oral administration and since long-term administration of the substances is required, a more agreeable and more reliable method of application must be provided for patients on whom injections and infusions, especially during therapy with anti-tumor drugs, put a heavy strain.
The transdermal administration of highly effective substances, such as, hormones, strong analgesics, nitrates, etc., has been known for several years.
Ondansetron is commercially available under the trade name Zofran(copyright) in a form suitable for injections or in the form of tablets for oral administration. At present, a form suitable for transdermal application does not exist.
WO 9825592, based on JP 96-346460, describes transdermal systems, which consist of at least three layers: (A) a xe2x80x9cbacking layerxe2x80x9d, which is impermeable for the active agent, (B) a layer which serves as a reservoir of the active agent and which contains a serotonin receptor antagonist, and (C) a layer which controls release of the active agent. This layer consists of a pressure-sensitive adhesive which controls release of the active agent.
WO 9407468, based on U.S. 92-956635, assigned to Cygnus Therapeutic Systems, USA, describes a xe2x80x9ctwo-phase matrix for sustained-release transdermal pharmaceuticalsxe2x80x9d as a transdermal system. The gist of this invention is that a second phase, which consists of hydrated inorganic silicate in the absorbed water phase of which a water-soluble active agent is dissolved, is dispersed in a hydrophobic continuous polymer, which optionally contains a hydrophobic solvent which is effective in enhancing permeation. For example, a matrix, which consists of 4 % (R)-(xe2x88x92)-N-(1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamided.2HCl, 10% propylene glycol monolaureate, 20% propylene glycol, 20% water, 7% calcium silicate, 2% Pluronic L-121 and dimethyl siloxane adhesive ad 100%, can be prepared by applying a solution of the above composition at a thickness of 250 xcexcm on a polyester film, drying and covering with a polyester film. The flow of the active agent through the human epidermis in a diffusion cell was 17.1 xcexcm/cm2/h in vitro, compared to 0.8 xcexcg/cm2/h for an adhesive matrix of styrene-butadiene copolymer which was used as a comparison.
At present, transdermal systems (which are to be understood in a broader sense, i.e. systems which in general are suitable for absorption through the skin) for 5-HT3 receptor antagonists do not exist.
The object of the invention is, therefore, to provide a transdermal system for release of 5-HT3 receptor antagonists which functions reliably and is kind to the skin and with which the disadvantages connected to the state of the art can be avoided.
This object is achieved according to the invention by a transdermal system for release of 5-HT3 receptor antagonists having the features recited in claim 1.
Further advantageous embodiments are subject matter of the dependent claims.
The invention also describes the use of the transdermal systems for release of 5-HT3 receptor antagonists according to the invention in anti-emetic treatment (i.e. for the treatment of nausea and emesis).